Structural insights into the mechanism of activation and inhibition of the prostaglandin D2 receptor 1

Behnaz Davoudinasab, Aleksey Raskovalov, Woojin Lee, Donggyun Kim, Heesoo Kim, Jordy Homing Lam, Gye Won Han, Vsevolod Katritch () and Vadim Cherezov ()
Additional contact information
Behnaz Davoudinasab: University of Southern California
Aleksey Raskovalov: University of Southern California
Woojin Lee: University of Southern California
Donggyun Kim: University of Southern California
Heesoo Kim: University of Southern California
Jordy Homing Lam: University of Southern California
Gye Won Han: University of Southern California
Vsevolod Katritch: University of Southern California
Vadim Cherezov: University of Southern California

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The prostaglandin D2 receptor 1 (DP1), a member of the prostanoid G protein-coupled receptor (GPCR) family, plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, we present five high-resolution cryo-electron microscopy (cryo-EM) structures of the human DP1 receptor, including an apo structure, two inactive state structures bound to two different inverse agonists developed by ONO Pharmaceutical, and two active state structures in complex with the Gs protein and bound to the endogenous agonist PGD2 and its selective derivative BW245C. Structural analysis, complemented by molecular dynamics simulations and site-directed mutagenesis, reveals key residues involved in ligand recognition and suggests a distinct activation mechanism for DP1, which lacks most of the conserved class A GPCR motifs. Notably, the unique residue K76 within the conserved sodium pocket acts as a major activation switch, while amphiphilic helix 8 adopts an unconventional orientation essential for receptor function. These findings offer valuable insights into the structure and function of prostanoid receptors and may facilitate the development of therapeutics targeting DP1.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-64002-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64002-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-64002-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().